Zlobec Inti, Baker Kristi, Terracciano Luigi M, Lugli Alessandro
Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
Clin Cancer Res. 2008 Jun 15;14(12):3798-806. doi: 10.1158/1078-0432.CCR-07-5103.
The aim of this study was to identify prognostic subgroups of microsatellite instability-high (MSI-H) colorectal cancers by combined analysis of 10 well-established immunohistochemical tumor markers and 7 clinicopathologic features.
Using a tissue microarray, immunohistochemistry was done on 223 cases of MSI-H cancers for the following protein markers: raf-1 kinase inhibitor protein, receptor for hyaluronic acid-mediated motility, apoptosis protease activating factor-1, mammalian sterile20-like kinase 1, p21, p27, p53, ephrin B2 receptor, Ki-67, and epidermal growth factor receptor. Seven clinicopathologic features and all tumor markers were evaluated in univariate and multivariable analyses.
RHAMM overexpression [P < 0.001; hazard ratio [HR; 95% confidence interval (95% CI)], 3.86 (2.19-6.81)], loss of p21 [P = 0.002; 0.33 (0.16-0.67)], and higher N stage [P < 0.001; 3.31 (1.9-5.8)] were independent adverse prognostic factors. RHAMM/p21 combinations were evaluated by N stage. Significant differences in survival were observed with various RHAMM/p21 combinations (P < 0.001). Both node-negative and node-positive patients with RHAMM- tumors survived more than 120 months. Node-positive RHAMM+ patients had a strikingly worse prognosis [16.0 (10.0-63.0) months] and could further be divided into p21- patients [14.0 (9.0-27.0) months] and p21+ patients surviving 47.0 months. RHAMM+/p21- node-negative patients had a significantly shorter survival time than RHAMM+/p21+ tumors (P = 0.021).
These results suggest that the combined phenotype of RHAMM and p21 expression is an invaluable independent prognostic immunohistochemical profile in MSI-H colorectal cancer. Based on the prognostic subgroups identified in our cohort, node-negative patients overexpressing RHAMM but with loss of p21 may derive a potential benefit from postoperative treatment, whereas adjuvant chemotherapy should be reconsidered for MSI-H node-positive RHAMM- tumors.
本研究旨在通过对10种成熟的免疫组化肿瘤标志物和7种临床病理特征进行联合分析，确定微卫星高度不稳定（MSI-H）结直肠癌的预后亚组。
使用组织芯片，对223例MSI-H癌症病例进行免疫组化检测，检测以下蛋白标志物：raf-1激酶抑制蛋白、透明质酸介导的运动受体、凋亡蛋白酶激活因子-1、哺乳动物 sterile20样激酶1、p21、p27、p53、 Ephrin B2受体、Ki-67和表皮生长因子受体。在单变量和多变量分析中评估了7种临床病理特征和所有肿瘤标志物。
RHAMM过表达[P < 0.001；风险比[HR；95%置信区间（95%CI）]，3.86（2.19 - 6.81）]、p21缺失[P = 0.002；0.33（0.16 - 0.67）]和更高的N分期[P < 0.001；3.31（1.9 - 5.8）]是独立的不良预后因素。根据N分期评估RHAMM/p21组合。不同的RHAMM/p21组合观察到生存存在显著差异（P < 0.001）。RHAMM-肿瘤的淋巴结阴性和阳性患者生存期均超过120个月。淋巴结阳性的RHAMM+患者预后明显更差[16.0（10.0 - 63.0）个月]，可进一步分为p21-患者[14.0（9.0 - 27.0）个月]和生存期为47.0个月的p21+患者。RHAMM+/p21-淋巴结阴性患者的生存时间明显短于RHAMM+/p21+肿瘤患者（P = 0.021）。
这些结果表明，RHAMM和p21表达的联合表型是MSI-H结直肠癌中一种非常有价值的独立预后免疫组化特征。基于我们队列中确定的预后亚组，过表达RHAMM但p21缺失的淋巴结阴性患者可能从术后治疗中获益，而对于MSI-H淋巴结阳性的RHAMM-肿瘤，应重新考虑辅助化疗。
